Game of clones: Battles in the field of carcinogenesis

Abstract

Recent advances in bulk sequencing approaches as well as genomic decoding at the single-cell level have revealed surprisingly high somatic mutational burdens in normal tissues, as well as increased our understanding of the landscape of "field cancerization", that is, molecular and immune alterations in mutagen-exposed normal-appearing tissues that recapitulated those present in tumors. Charting the somatic mutational landscapes in normal tissues can have strong implications on our understanding of how tumors arise from mutagenized epithelium. Making sense of those mutations to understand the progression along the pathologic continuum of normal epithelia, preneoplasias, up to malignant tissues will help pave way for identification of ideal targets that can guide new strategies for preventing or eliminating cancers at their earliest stages of development. In this review, we will provide a brief history of field cancerization and its implications on understanding early stages of cancer pathogenesis and deviation from the pathologically "normal" state. The review will provide an overview of how mutations accumulating in normal tissues can lead to a patchwork of mutated cell clones that compete while maintaining an overall state of functional homeostasis. The review also explores the role of clonal competition in directing the fate of normal tissues and summarizes multiple mechanisms elicited in this phenomenon and which have been linked to cancer development. Finally, we highlight the importance of understanding mutations in normal tissues, as well as clonal competition dynamics (in both the epithelium and the microenvironment) and their significance in exploring new approaches to combatting cancer.

Keywords: Clonal competition; Field cancerization; Field carcinogenesis; Somatic mutations; cancer evolution.

Fig. 1.. The evolution of clones in mutagenized cancerization fields.

Mutagen exposure (e.g., cigarette smoking) over time induces random somatic mutations in normal tissues. The tissue adopts a multifocal spatial pattern followed by expansion of small patches comprising a group of cells that share a common ancestor. This field of mutating clones is referred to as the airway field of injury, and it is evident in lung epithelium of cancer-free individuals at increased risk for lung cancer and who have had a long period of tobacco exposure (middle panel). Mutant clones might not necessarily lead to overt malignancy. However, a clonal unit or patch may acquire additional tissue-relevant genetic alterations in the proper microenvironment that provide a growth advantage, thus gradually enabling the conversion of that clonal patch into a tumorigenic one. Normal appearing tissues surrounding the tumor harbor some but not all phenotypic traits entailed for malignancy, a phenomenon named “field of cancerization” (right panel). Colored patches represent different mutant clones in the airway field of injury. Concentric patches surrounding the tumor depict the field of cancerization. Created with BioRender.com.

Fig. 2.. Outcomes of clonal competition.

This schematic representation depicts different scenarios of clonal competition based on the relative fitness of cells and clonal advantage. Going from left to right, neighboring cells compete and the relative fitness of each cell (clonal advantage) determines the outcome of competition. In the most common scenario, wild-type normal cells (yellow) tend to be crowned as winners when competing with their mutant counterparts (pink). However, some genetic mutations may confer a competitive advantage to the mutant cells which then eliminate wild-type cells and dominate the field. Further transformation of mutant normal cells into tumor ones (red) can have two outcomes depending on relative fitness. It is possible that neoantigen expression can modulate recognition of mutant cells (normal mutant or tumor mutant) by the immune system, which can alter the outcome of the competition, thereby emphasizing the importance of the microenvironment in elimination of early tumorigenesis. If normal mutant cells have a superior clonal advantage, they can dominate the field, maintaining homeostasis and normal tissue function. Alternatively, and under the appropriate conditions, less fit mutant cells can be displaced by mutant tumor cells leading to expansion and formation of an invasive tumor. Created with BioRender.com